| Reference | 1. Front Oncol. 2019 Apr 25;9:313. doi: 10.3389/fonc.2019.00313. eCollection 2019.
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Glesatinib, a c-MET/SMO Dual Inhibitor, Antagonizes P-glycoprotein Mediated
Multidrug Resistance in Cancer Cells.
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Cui Q(1)(2), Cai CY(2), Gao HL(2)(3), Ren L(1), Ji N(2)(4), Gupta P(2), Yang
Y(2), Shukla S(5), Ambudkar SV(5), Yang DH(2), Chen ZS(2).
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Author information:
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(1)School of Public Health, Guangzhou Medical University, Guangdong, China.
(2)Department of Pharmaceutical Sciences, College of Pharmacy and Health
Sciences, St. John’s University, Queens, NY, United States.
(3)Department of Histology and Embryology, Clinical Medical College, Weifang
Medical University, Weifang, China.
(4)Tianjin Key Laboratory on Technologies Enabling Development of Clinical
Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University,
Tianjin, China.
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(5)Laboratory of Cell Biology, Center for Cancer Research, National Cancer
Institute, NIH, Bethesda, MD, United States.
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Multidrug resistance (MDR) is one of the leading causes of treatment failure in
cancer chemotherapy. One major mechanism of MDR is the overexpressing of ABC
transporters, whose inhibitors hold promising potential in antagonizing MDR.
Glesatinib is a dual inhibitor of c-Met and SMO that is under phase II clinical
trial for non-small cell lung cancer. In this work, we report the reversal
effects of glesatinib to P-glycoprotein (P-gp) mediated MDR. Glesatinib can
sensitize paclitaxel, doxorubicin, colchicine resistance to P-gp overexpressing
KB-C2, SW620/Ad300, and P-gp transfected Hek293/ABCB1 cells, while has no effect
to their corresponding parental cells and negative control drug cisplatin.
Glesatinib suppressed the efflux function of P-gp to [3H]-paclitaxel and it
didn’t impact both the expression and cellular localization of P-gp based on
Western blot and immunofluorescent analysis. Furthermore, glesatinib can
stimulate ATPase in a dose-dependent manner. The docking study indicated that
glesatinib interacted with human P-gp through several hydrogen bonds. Taken
together, c-Met/SMO inhibitor glesatinib can antagonize P-gp mediated MDR by
inhibiting its cell membrane transporting functions, suggesting new application
in clinical trials.
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2. Clin Cancer Res. 2017 Nov 1;23(21):6661-6672. doi: 10.1158/1078-0432.CCR-17-1192.
Epub 2017 Aug 1.
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Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients
Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to
Type I MET Inhibitors in Nonclinical Models.
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Engstrom LD(1), Aranda R(1), Lee M(1), Tovar EA(2), Essenburg CJ(2), Madaj Z(2),
Chiang H(1), Briere D(1), Hallin J(1), Lopez-Casas PP(3), Baños N(3), Menendez
C(3), Hidalgo M(3), Tassell V(1), Chao R(1), Chudova DI(4), Lanman RB(4), Olson
P(1), Bazhenova L(5), Patel SP(5), Graveel C(2), Nishino M(6), Shapiro GI(7),
Peled N(8), Awad MM(7), Jänne PA(7), Christensen JG(9).
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Author information:
(1)Mirati Therapeutics, Inc., San Diego, California.
(2)Van Andel Research Institute, Grand Rapids, Michigan.
(3)Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer
Research Centre), Madrid, Spain.
(4)Guardant Health, Inc., Redwood City, California.
(5)Moores Cancer Center, University of California, San Diego, San Diego,
California.
(6)Department of Radiology, Brigham and Women’s Hospital and Dana-Farber Cancer
Institute, Boston, Massachusetts.
(7)Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts.
(8)Sheba Medical Center, Tel-Aviv University, Ramat-Gan, Israel.
(9)Mirati Therapeutics, Inc., San Diego, California. [email protected].
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Purpose:MET exon 14 deletion (METex14 del) mutations represent a novel class of
non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a
spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14
del-positive nonclinical models and NSCLC patients and assessed its ability to
overcome resistance to type I MET inhibitors.Experimental Design: As most MET
inhibitors in clinical development bind the active site with a type I binding
mode, we investigated mechanisms of acquired resistance to each MET inhibitor
class utilizing in vitro and in vivo models and in glesatinib clinical
trials.Results: Glesatinib inhibited MET signaling, demonstrated marked
regression of METex14 del-driven patient-derived xenografts, and demonstrated a
durable RECIST partial response in a METex14 del mutation-positive patient
enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical
models with selected MET inhibitors resulted in differences in resistance
kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H)
that conferred resistance to type I MET inhibitors, but remained sensitive to
glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and
resistance to type I inhibitors exhibited a marked response to glesatinib.
Finally, a METex14 del mutation-positive NSCLC patient who responded to
crizotinib but later relapsed, demonstrated a mixed response to glesatinib
including reduction in size of a MET Y1230H mutation-positive liver metastasis
and concurrent loss of detection of this mutation in plasma DNA.Conclusions:
Together, these data demonstrate that glesatinib exhibits a distinct mechanism of
target inhibition and can overcome resistance to type I MET inhibitors. Clin
Cancer Res; 23(21); 6661-72. ©2017 AACR.
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